Search Results (19,189)

Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management. Full article

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are hereditary haemoglobinopathies characterized by a reduction in functional β-globin chains. Both conditions cause tiredness and increase susceptibility to infection, which can lead organ failure, significantly reducing life expectancy and typically requiring those affected to undergo regular erythrocyte transfusion. Recently, a novel therapeutic treatment for SCD and TDT was approved by the UK regulatory body (Medicines and Healthcare products Regulatory Agency; MHRA). Exagamglogene autotemcel (Casgevy) is the first licensed therapy globally to utilize CRIPSR/Cas9 technology and induces an increase in expression of γ-globin chains to compensate for the reduction in functional β-globin. Casgevy represents a first-in-class therapeutic, and numerous considerations were made by the MHRA throughout its assessment of the medicine. These include, but are not limited to, the risk of tumorigenicity and off-target editing, a limited cohort size, the validity of proposed dosing and the conduction of only single-arm studies. The MHRA’s analyses of the data to support the proposed indications are presented and discussed throughout this manuscript. Overall, the sponsors claims were considered well supported by their data, and Casgevy was licensed for the treatment of TDT or SCD in patients 12 years of age and older for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen-matched related HSC donor is not available. Full article

This study investigates whether hAFSCs can improve bladder function in partial bladder outlet obstruction (pBOO) rats by targeting specific cellular pathways. Thirty-six female rats were divided into sham and pBOO groups with and without hAFSCs single injection into the bladder wall. Cystometry, inflammation/hypoxia, collagen/fibrosis/gap junction proteins, and smooth muscle myosin/muscarinic receptors were examined at 2 and 6 weeks after pBOO or sham operation. In pBOO bladders, significant increases in peak voiding pressure and residual volume stimulated a significant upregulation of inflammatory and hypoxic factors, TGF-β1 and Smad2/3. Collagen deposition proteins, collagen 1 and 3, were significantly increased, but bladder fibrosis markers, caveolin 1 and 3, were significantly decreased. Gap junction intercellular communication protein, connexin 43, was significantly increased, but the number of caveolae was significantly decreased. Markers for the smooth muscle phenotype, myosin heavy chain 11 and guanylate-dependent protein kinase, as well as M2 muscarinic receptors, were significantly increased in cultured detrusor cells. However, hAFSCs treatment could significantly ameliorate bladder dysfunction by inactivating the TGFβ-Smad signaling pathway, reducing collagen deposition, disrupting gap junctional intercellular communication, and modifying the expressions of smooth muscle myosin and caveolae/caveolin proteins. The results support the potential value of hAFSCs-based treatment of bladder dysfunction in BOO patients. Full article

Without proven causal power, consciousness cannot be integrated with physics except as an epiphenomenon, hence the term ‘hard problem’. Integrated Information Theory (IIT) side-steps the issue by stating that subjective experience must be identical to informational physical structures whose cause-and-effect power is greater than the sum of their parts. But the focus on spatially oriented structures rather than events in time introduces a deep conceptual flaw throughout its entire structure, including the measure of integrated information, known as Φ (phi). However, the problem can be corrected by incorporating the temporal feature of consciousness responsible for the hard problem, which can ultimately resolve it, namely, that experiencer and experienced are not separated in time but exist simultaneously. Simultaneous causation is not possible in physics, hence the hard problem, and yet it can be proven deductively that consciousness does have causal power because of this phenomenological simultaneity. Experiencing presence makes some facts logically possible that would otherwise be illogical. Bypassing the hard problem has caused much of the criticism that IIT has attracted, but by returning to its roots in complexity theory, it can repurpose its model to measure causal connections that are temporally rather than spatially related. Full article

Cuttlefish bones are byproducts of cuttlefish processing and are readily available in the marine food industry. In this study, calcium phosphate bioceramics were prepared from cuttlefish bones using a two−stage hydrothermal calcination process. The results indicated that all bioceramics derived from cuttlefish bones had a higher degradation capacity, better bone−like apatite formation ability, and higher degree of osteogenic differentiation than commercially available hydroxyapatite. Notably, β−tricalcium phosphate, which had the highest degree of Ca²⁺ and Sr²⁺ dissolution among the bioceramics extracted, can significantly upregulate osteogenic markers (alkaline phosphatase, osteocalcin) and stimulate bone matrix mineralization. Thus, it is a promising bioceramic material for applications in bone regeneration. Full article

Vaccine-preventable diseases continue to generate a substantial burden on health, healthcare systems, and societies, which is projected to increase with population ageing. There is a need to better understand the full value of adult immunisation programmes corresponding to the broader value of vaccine frameworks that are recommended for evidence-based decision-making. This review aims to summarise and map evidence for the value of selected adult immunisation programmes (seasonal influenza, pneumococcal disease, RSV, and HZ) in ten diverse countries. We conducted a structured literature review of evidence published from 2017 to 2023. An existing framework was used to structure the assessment, developing matrices demonstrating the elements of value evidenced for each vaccine and country of focus. Our analysis showed substantial evidence base on the value of adult immunisation programmes, but the availability of evidence varied by value element and by vaccine. The impact on the quality of life of the vaccinated individual was the most evidenced value element. Mortality benefits for vaccinated individuals and cost-offsets to healthcare systems were also well-evidenced. The availability of evidence for ‘broader’ societal value elements (such as transmission value, carer productivity and impact on social equity, and antimicrobial resistance prevention) varied. No evidence was identified relating to the broader value elements of macroeconomic effects, value to other interventions, or effects on the quality of life of caregivers. Robust evidence exists to show that adult immunisation programmes generate substantial value for population health and health systems, yet some elements of broader value remain underrepresented in the academic literature. Without such evidence, the full value of immunisation programmes is underestimated, risking suboptimal policy decisions. Full article

Metastatic gastric cancer (GC) still represents a critical clinical challenge, with limited treatment options and a poor prognosis. Most patients are diagnosed at advanced stages, limiting the chances of surgery and cure. The identification of molecular targets and the possibility of combining immune checkpoint inhibitors with chemotherapy have recently reshaped the therapeutic landscape of metastatic gastric cancer. The new classification of gastric cancer, mainly based on immunologic and molecular criteria such as programmed cell death 1 (PD-1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), has made it possible to identify and differentiate patients who may benefit from immunotherapy, targeted therapy, or chemotherapy alone. All relevant and available molecular and immunological targets in clinical practice for the systemic treatment of this disease are presented. Particular attention is given to possible future approaches, including circulating tumor DNA (ctDNA) for therapeutic monitoring, new targeting agents against molecular pathways such as fibroblast growth factor receptor (FGFR) and MET, chimeric antigen receptor (CAR)-T cells, and cancer vaccines. This review aims to provide a comprehensive understanding of current targets in advanced gastric cancer and to offer valuable insights into future directions of research and clinical practice in this challenging disease. Full article

Cancer, a multifactorial disease characterized by uncontrolled cellular proliferation, remains a global health challenge with significant morbidity and mortality. Genomic and molecular aberrations, coupled with environmental factors, contribute to its heterogeneity and complexity. Chemotherapeutic agents like doxorubicin (Dox) have shown efficacy against various cancers but are hindered by dose-dependent cytotoxicity, particularly on vital organs like the heart and brain. Autophagy, a cellular process involved in self-degradation and recycling, emerges as a promising therapeutic target in cancer therapy and neurodegenerative diseases. Dysregulation of autophagy contributes to cancer progression and drug resistance, while its modulation holds the potential to enhance treatment outcomes and mitigate adverse effects. Additionally, emerging evidence suggests a potential link between autophagy, DNA damage, and caretaker breast cancer genes BRCA1/2, highlighting the interplay between DNA repair mechanisms and cellular homeostasis. This review explores the intricate relationship between cancer, Dox-induced cytotoxicity, autophagy modulation, and the potential implications of autophagy in DNA damage repair pathways, particularly in the context of BRCA1/2 mutations. Full article

Peptides are gaining prominence in various fields, including the pharmaceutical industry. To meet regulatory requirements, they must achieve a certain purity threshold to ensure safe administration. Numerous purification technologies have been employed to purify peptides, aiming to reduce cost and time while being sustainable and efficient. These include chromatography, magnetic nanoparticles, isoelectric focusing, and membrane filtration. The physicochemical properties of peptides are the main driving element behind these technologies. While chromatographic separation remains the gold standard for peptide separation and purification, with various models to predict the elution behaviors of peptides, other technologies have demonstrated their capability to meet the performance of established chromatographic methodologies, with better productivity and reduced cost. This opens the door for further investigational studies to assess these outcomes and potentially introduce new techniques for peptide purification. In this review, we examine these technologies in terms of their efficiency and their ability to meet sustainability requirements, concluding with remarks and an outlook on future advancements. Full article

Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time. Cross- and side-bridged tetraazamacrocylic complexes offer significant advantages over the non-bridged molecular structures in terms of receptor affinity, potential for radiolabelling, and use in therapeutic applications. Our investigation has been extended to the influence of the ring size on bridged tetraazamacrocyclic compounds with the addition of two novel chelators (bis-cross-bridged homocyclen and bis-cross-bridged cyclen) to compare to the bis-bridged cyclam, along with novel metal complexes formed with copper(II) or zinc(II). The in vitro biological assays showed that all of the zinc(II) complexes are high affinity antagonists with a marked increase in CXCR4 selectivity for the bis-cross-bridged cyclen complex, whereas the properties of the copper(II) complexes are highly dependent on metal ion geometry. X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics. Full article

The “Management Competencies to Prevent and Reduce Stress at Work” (MCPARS) approach focuses on identifying the stress-preventive managers’ competencies able to optimise the employees’ well-being through the management of the psychosocial work environment. Considering leadership as contextualised in complex social dynamics, the self–other agreement (SOA) investigation of the MCPARS may enhance previous findings, as it allows for exploring the manager–team perceptions’ (dis)agreement and its potential implications. However, no studies have tested the MCPARS using the SOA and multisource data. Grounded in Yammarino and Atwater’s SOA reference theory, we conducted an in-depth investigation on the MCPARS’s theoretical framework by examining the implications of manager–team (dis)agreement, regarding managers’ competencies, on employees’ psychosocial environment (H1–H2) and affective well-being (H3). Data from 36 managers and 475 employees were analysed by performing several polynomial regressions, response surface, and mediation analyses. The results reveal a significant relationship between SOA on MCPARS and employees’ perceptions of the psychosocial environment (H1). Employees report better perceptions when supervised by in-agreement good or under-estimator managers, while lower ratings occur under over-estimator or in-agreement poor managers (H2). Moreover, the psychosocial environment significantly mediated the relationship between SOA on MCPARS and employees’ well-being (H3). The MCPARS theoretical model’s soundness is supported, and its implications are discussed. Full article

The evaluation of ecosystem service value (ESV) is crucial for decision making in regional sustainable development. The close relationship between ecosystem services and land use/cover change (LUCC) is well acknowledged. However, the impact of the mutual transformation among different land use types on the temporal and spatial differences in the ESV is still unclear. To fulfill this gap, this study evaluates the ESV in the Wuhan Urban Agglomerations based on LUCC, taking the spatiotemporal characteristics into consideration. The results show that (1) The land use structure in the Wuhan Urban Agglomerations has undergone great changes from 2012 to 2021, and the area of cultivated land converted to forest land is the largest, which may be related to policies such as returning farmland to forests. (2) The total amount of ESV shows a downward trend, and the spatial distribution of ESV is “low in the west and high in the central and eastern regions”, which may be related to the natural factors in study area. (3) The spatial distribution of ESV in the study area will remain unchanged in the future. However, the transformation among land use types may exacerbate the reduction in the total ESV, which will have an adverse impact on the ecological environment and sustainable development of the region. This study initiates a more comprehensive framework to better reflect the real scenario of ESV, which will hopefully provide a reference for regional sustainable development. Full article

This paper presents a novel adaptation of the conventional approximate Bayesian computation sequential Monte Carlo (ABC-SMC) sampling algorithm for parameter estimation in the presence of uncertainties, coined combinatorial ABC-SMC. Inference of this type is used in situations where there does not exist a closed form of the associated likelihood function, which is replaced by a simulating model capable of producing artificial data. In the literature, conventional ABC-SMC is utilised to perform inference on continuous parameters. The novel scheme presented here has been developed to perform inference on parameters that are high-dimensional binary, rather than continuous. By altering the form of the proposal distribution from which to sample candidates in subsequent iterations (referred to as waves), high-dimensional binary variables may be targeted and inferred by the scheme. The efficacy of the proposed scheme is demonstrated through application to vibration data obtained in a structural dynamics experiment on a fibre-optic sensor simulated as a finite plate with uncertain boundary conditions at its edges. Results indicate that the method provides sound inference on the plate boundary conditions, which is validated through subsequent application of the method to multiple vibration datasets. Comparisons between appropriate forms of the metric function used in the scheme are also developed to highlight the effect of this element in the schemes convergence. Full article

We present contrast information, a novel application of some specific cases of relative entropy, designed to be useful for the cognitive modelling of the sequential perception of continuous signals. We explain the relevance of entropy in the cognitive modelling of sequential phenomena such as music and language. Then, as a first step to demonstrating the utility of constrast information for this purpose, we empirically show that its discrete case correlates well with existing successful cognitive models in the literature. We explain some interesting properties of constrast information. Finally, we propose future work toward a cognitive architecture that uses it. Full article

The reliable operation of a power system requires a real-time balance between supply and demand. However, it is difficult to achieve this balance solely by relying on supply-side regulation. Therefore, it is necessary to cooperate with effective demand-side management, which is a key strategy within smart grid systems, encouraging end-users to actively engage and optimize their electricity usage. This paper proposes a novel bi-level optimization model for integrating solar, hydrogen, and battery storage systems with charging stations (SHS-EVCSs) to maximize social welfare. The first level employs a non-cooperative game theory model for each individual EVCS to minimize capital and operational costs. The second level uses a cooperative game framework with an internal management system to optimize energy transactions among multiple EVCSs while considering EV owners’ economic interests. A Markov decision process models uncertainties in EV charging times, and Monte Carlo simulations predict charging demand. Real-time electricity pricing based on the dual theory enables demand-side management strategies like peak shaving and valley filling. Case studies demonstrate the model’s effectiveness in reducing peak loads, balancing energy utilization, and enhancing overall system efficiency and sustainability through optimized renewable integration, energy storage, EV charging coordination, social welfare maximization, and cost minimization. The proposed approach offers a promising pathway toward sustainable energy infrastructure by harmonizing renewable sources, storage technologies, EV charging demands, and societal benefits. Full article